Methods for treating bowel diseases

ABSTRACT

The present invention provides new methods of treating bowel disease (BD) by increasing a durability of response; treating BD in males; treating BD in adolescent subjects; treating bloating due to BD in males; and methods of maintaining remission of BD.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/650,188, filed Oct. 12, 2012, which is a continuation of U.S. patentapplication Ser. No. 12/393,979, filed Feb. 26, 2009, now U.S. Pat. No.8,309,569, which claims the benefit of U.S. Provisional Applications61/031,679 and U.S. 61/102,801 filed Feb. 26, 2008 and Oct. 3, 2008,respectively. The entire contents of the aforementioned applications areexpressly incorporated herein by reference.

BACKGROUND

Rifaximin (INN; see The Merck Index, XIII Ed., 8304) is an antibioticbelonging to the rifamycin class of antibiotics, e.g., a pyrido-imidazorifamycin. Rifaximin exerts its broad antibacterial activity, forexample, in the gastrointestinal tract against localizedgastrointestinal bacteria that cause infectious diarrhea, irritablebowel syndrome, small intestinal bacterial overgrowth, Crohn's disease,and/or pancreatic insufficiency. It has been reported that rifaximin ischaracterized by a negligible systemic absorption, due to its chemicaland physical characteristics (Descombe J. J. et al. Pharmacokineticstudy of rifaximin after oral administration in healthy volunteers. IntJ Clin Pharmacol Res, 14 (2), 51-56, (1994)).

SUMMARY

Disclosed herein are methods of preventing, ameliorating and/or treatingbowel diseases (BDs). In general, subjects who may benefit fromtreatment with a rifamycin class antibiotic (e.g., rifaximin) includethose who are susceptible to BDs, those who have active or acutediseases and those who are in remission from one or more BDs. BDsinclude, for example, irritable bowel syndrome (IBS), uncontrolleddiarrhea-associated Irritable Bowel Syndrome (dIBS), Crohn's disease,traveler's diarrhea, ulcerative colitis, enteritis, small intestinalbacterial overgrowth, chronic pancreatitis, pancreatic insufficiency,colitis, diverticular disease and/or hepatic encephalopathy. Subjectswho may particularly benefit from this treatment include those who areor may be suffering from or susceptible to IBS.

In one aspect, presented herein are methods of treating bowel disease(BD) with a durability of antibiotic response, comprising administeringa therapeutically effective amount of a rifamycin class antibiotic to asubject in need thereof, selecting subjects who respond to treatmentafter being treated for between about 1 and about 24 weeks, and removinga responding subject from treatment wherein after removal of treatmentthere is a durability of response.

In one embodiment, the bowel disease comprises Irritable Bowel Syndrome(IBS).

In one embodiment, the bowel disease comprises diarrhea-associatedIrritable Bowel Syndrome (dIBS).

In one embodiment, the bowel disease comprises hepatic encephalopathy.

In another embodiment, hepatic encephalopathy (HE) will be administereda rifamycin class antibiotic for between about 28 days weeks and 24months. In treating HE, the rifamycin class antibiotic may beadministered for as long a necessary, for example, for 12 months andlonger, or for a subject's entire life span, for example, after beingsuspected of or diagnosed as having HE.

In one embodiment, at least 50% of patients respond.

In one embodiment, the therapeutically effective amount comprises frombetween about 25 mg to about 6000 mg.

In one embodiment, the therapeutically effective amount comprises 550 mgTID.

In one embodiment, the therapeutically effective amount comprises 550 mgBID.

In one embodiment, the therapeutically effective amount comprises 600 mgTID.

In one embodiment, the therapeutically effective amount comprises 600 mgBID.

In one embodiment, the therapeutically effective amount comprises 1650mg/day.

In one embodiment, the BD comprises uncontrolled diarrhea-associatedirritable bowel syndrome (dIBS).

In one embodiment, the rifamycin class antibiotic comprises a compoundof Formula I.

In one embodiment, the rifamycin class antibiotic comprises rifaximin.

In one embodiment, subjects are treated from between about 7 days andabout 4 weeks prior to selection.

In one embodiment, the subject is selected upon response to therifamycin class antibiotic.

In one embodiment, the subject is selected when response to therifamycin class antibiotic is recognized.

In one embodiment, the durability of response comprises from at leastbetween about 1 and about 24 weeks of adequate relief of symptoms.

In one embodiment, the durability of response comprises from at leastbetween about 1 and about 5 weeks of adequate relief of symptoms.

In one embodiment, symptoms comprise one or more of overall BD symptomsor bloating.

In one embodiment, adequate relief of BD symptoms comprises a reductionof BD symptoms.

In one embodiment, the reduction in BD symptoms is a reduction frombaseline symptoms.

In one embodiment, baseline symptoms are established prior to treatment.

In one embodiment, adequate relief of BD symptoms comprises a ‘yes’response from a subject when asked the question comprising or similarto, “In the past 7 days, have you had adequate relief of your symptom ofyour BD symptoms?” In one embodiment, adequate relief of BD symptomscomprises an affirmative response (e.g., yes) from a subject if askedweather they have had adequate relief of symptom of BD.

In one embodiment, BD symptoms comprise one or more of cramping, pain,diarrhea, constipation, lumpy stool, watery stool, frequent stoolproduction, abdominal pain, abdominal discomfort, and/or urgency.

In one embodiment, wherein adequate relief of bloating symptomscomprises a reduction of bloating symptoms.

In one embodiment, wherein the reduction in bloating symptoms is areduction from baseline symptoms.

In one embodiment, baseline symptoms are established prior to treatment.

In one embodiment, adequate relief of bloating symptoms comprises a‘yes’ response from a subject when asked the question comprising orsimilar to “In the past 7 days, have you had adequate relief of yoursymptom of bloating?” In one embodiment, adequate relief of BD symptomscomprises an affirmative response (e.g., yes) from a subject if asked aweather they have had adequate relief of bloating.

In one embodiment, bloating symptoms comprise one or more of thesymptoms of abdominal fullness, bloating, gas, or swelling.

In one embodiment, a BD comprises one or more of irritable bowelsyndrome (IBS), uncontrolled diarrhea-associated Irritable BowelSyndrome (dIBS), Crohn's disease, traveler's diarrhea, ulcerativecolitis, enteritis, small intestinal bacterial overgrowth, chronicpancreatitis, pancreatic insufficiency, colitis, diverticular disease,hepatic encephalopathy, and/or or pouchitis.

In one embodiment, a BD may also comprise one or more of fibromyalgia(FM), chronic fatigue syndrome (CFS), depression, attentiondeficit/hyperactivity disorder (ADHD), multiple sclerosis (MS), and/orsystemic lupus erythematosus (SLE).

In one aspect, presented herein are methods of treating bowel disease(BD) in males comprising, administering a therapeutically effectiveamount of rifaximin to a male in need thereof.

In one embodiment, the methods further comprise determining the genderof a subject and administering the therapeutically effective amount to amale subject.

In one embodiment, the methods further comprise determining symptomrelief in the male subject and administering a second course ofrifaximin treatment if symptoms remain unresolved.

In one aspect, presented herein are methods of treating bloating due toBD in males comprising administering a therapeutically effective amountof rifaximin to a male in need thereof.

In one aspect, presented herein are methods of treating BD in oldersubjects comprising administering a therapeutically effective amount ofrifaximin to an older subject in need thereof, determining symptomrelief in the older subject and administering a second course ofrifaximin treatment if symptoms were unresolved. As used herein, anolder subject, refers for example to a subject >65 years of age, asubject about 50 years of age or older, a subject about 55 years of ageor older, a subject about 60 years of age or older, or a subject about70 years of age or older. A “long duration of disease,” as used hereinrefers, for example, to a subject suffering from the disease for about 4to about >10 years, or to a subject suffering from the disease fromabout 5 years to about 10 years, or to a subject suffering from thedisease from about 5 years to about 20 years or greater.

In one aspect, presented herein are methods of predicting response torifaximin treatment for BD comprising: assessing a subject sufferingfrom BD and administering a therapeutically effective amount ofrifaximin to one or more of a subject determined to be old, with longduration of BD, men or those having a baseline severity of mild tomoderate.

In one embodiment, the method further comprises determining, based onclinical data, weather a subject will have a positive response totreatment. In one embodiment, the determination is made based on one ormore of a subject's age, a subject's duration of BD, gender, or baselineseverity of BD. In one embodiment, the clinical data is presented in alabel on a pharmaceutical product.

In one embodiment, if a subject is male, there is a prediction ofresponse.

In one embodiment, if a subject is older, there is a prediction ofresponse.

In one embodiment, if a subject has had a long duration of disease,there is a prediction of response.

In one embodiment, baseline severity determination comprises a 7-pointLickert scale.

In one embodiment, the methods further comprise notifying the subject ofa likelihood of response.

In one embodiment, a subject's likelihood of response increases with ageand with length of duration of BD.

In one embodiment, the therapeutically effective amount comprises frombetween about 100 mg and about 6000 mg; 550 mg TID; 550 mg BID; 600 mgTID; 600 mg BID; or 1650 mg.

In one aspect, presented herein are methods of treating BD, comprising:providing a container comprising a rifamycin class antibiotic, whereinthe container comprises printed labeling which describes a durability ofantibiotic response and suggests selecting subject's who respond totreatment have a durability of response after removal from treatment;and administering rifaximin from the container to the subject.

In one embodiment, the rifamycin class antibiotic comprises rifaximin.

In one aspect, presented herein are kits for treating BD comprising acontainer comprising a rifamycin class antibiotic and a label whichdescribes that administration of a therapeutically effective amount ofthe antibiotic results in a durability of response in a subject thatresponds to the treatment.

In one embodiment, the label describes adverse events comprising one ormore of infections and infestations, gastrointestinal disorders, nervoussystem disorders, and musculoskeletal and connective tissue disorders.

In one embodiment, the label describes a length of treatment with therifamycin class antibiotic, whereby a subject is selected as respondingto treatment if a healthcare professional prescribes the rifamycin classantibiotic according to the label instructions.

In one embodiment, the label describes a length of treatment with therifamycin class antibiotic, whereby a subject is removed from treatmentif a healthcare professional prescribes the rifamycin class antibioticaccording to the label instructions.

In one aspect, the rifamycin class antibiotic comprises one or more ofrifaximin or a Form α, Form β, Form γ, Form γ, Form ε, Form ζ, Form η,Form α-dry, Form ι, Form β-1, Form β-2, Form ε-dry, mesylate Form oramorphous Forms of rifaximin and a pharmaceutically acceptable carrier.The rifaximin may be formulated as a pharmaceutical composition. In oneembodiment, the rifamycin class antibiotic comprises rifaximin.

In one embodiment, the pharmaceutical composition further comprisesexcipients.

According to another embodiment, the excipients comprise one or more ofa diluting agent, binding agent, lubricating agent, disintegratingagent, coloring agent, flavorings agent or sweetening agent.

In another embodiment, the composition is formulated for selected coatedand uncoated tablets, hard and soft gelatin capsules, sugar-coatedpills, lozenges, wafer sheets, pellets and powders in sealed packet. Inone embodiment, the composition is formulated for topical use.

According to another embodiment, the bowel related disorder is one ormore of irritable bowel syndrome (IBS), uncontrolled diarrhea-associatedIrritable Bowel Syndrome (dIBS), Crohn's disease, traveler's diarrhea,ulcerative colitis, enteritis, small intestinal bacterial overgrowth,chronic pancreatitis, pancreatic insufficiency, colitis, diverticulardisease, hepatic encephalopathy, and/or or pouchitis.

According to one aspect, provided herein are methods of improving QOLmeasures in a BD subject comprising administering rifaximin.

According to one aspect, provided herein are methods of improving QOLmeasures in a BD subjects comprising administering a rifamycin classantibiotic.

In one embodiment, rifaximin is administered for 14 days.

In one embodiment, one or more of quality of life measures comprisingdysphoria, body image, health worry, social reaction, and relationshipare improved upon administration of rifaximin.

In one embodiment, selecting comprises following dosing instructions ona package insert of a pharmaceutical product.

In one embodiment, the package insert instructs to administer therifamycin class antibiotic for 14 days.

In one embodiment, removing comprises instructing a subject by followingdosing instructions on a package insert of a pharmaceutical product.

In one embodiment, the package insert instructs to administer therifamycin class antibiotic for 14 days.

In one embodiment, the product comprises 550 mg of rifaximin labeled fortreatment of irritable bowel syndrome.

In one embodiment, the product comprises 550 mg of rifaximin labeled fortreatment of hepatic encephalopathy.

In one embodiment, the product comprises 600 mg of rifaximin labeled fortreatment of irritable bowel syndrome.

In one embodiment, the product comprises 600 mg of rifaximin labeled fortreatment of hepatic encephalopathy.

In one embodiment, the product comprises 550 mg of rifaximin labeled fortreatment of one or more of irritable bowel syndrome, Travelers'diarrhea or hepatic encephalopathy.

In one embodiment, the product comprises 550 mg of rifaximin.

In one embodiment, the product comprises 600 mg of rifaximin.

In one embodiment, the product comprises 200 mg of rifaximin.

In one embodiment, the product comprises 400 mg of rifaximin.

In one embodiment, the product comprises 400 mg of rifaximin BID.

In one embodiment, the product comprises 400 mg of rifaximin TID.

In one embodiment, the method further comprises determining risk of BDin a subject prior to administration of the rifamycin class antibioticby genetically profiling the subject risk of BD and selecting toadminister a rifamycin class antibiotic to an at risk subject.

In one embodiment, determining risk comprises determining polymorphismsat one or more of Nod2, CFTR, CARD15, rs6822844, rs2305767, rs6822844,8q24 region; Marker:rs6983267, LOC727677, IL23R(1), NKX2-3, 5p13 region,PTPN2, MST1, IRGM, IL23R(2), or 10q21 region.

Provided herein, according to one aspect are methods of providing acutetreatment for symptomatic diarrhea-associated Irritable Bowel Syndrome(dIBS) comprising: administering 1650 mg/day of rifaximin for 14 days toa subject in need thereof, wherein removing the subject from treatmentafter the 14 days results in a durability of response.

In one embodiment, the 1650 mg is administered as 550 mg three times aday.

Provided herein, according to one aspect are methods of providing acutetreatment for uncontrolled diarrhea-associated Irritable Bowel Syndrome(dIBS) comprising: administering 550 mg rifaximin two or three times aday for two weeks to a subject in need thereof, wherein removing thesubject from treatment after the two weeks results in a durability ofresponse.

In one embodiment, the treatment provides symptomatic relief of dIBS.

In one embodiment, a package insert of a pharmaceutical product warns ofadverse events, including, for example, infections and infestations,gastrointestinal disorders, nervous system disorders, andmusculoskeletal and connective tissue disorders.

Other embodiments of the invention are disclosed infra.

DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a graph of continuous adequate relief of IBS symptomsduring non-treatment follow-up.

FIG. 2 shows a graph of continuous adequate relief of bloating symptomsduring non-treatment follow-up.

FIG. 3 shows proposed study design for treatment with rifaximin to showdurability of response.

FIG. 4 shows graphical results of adequate relief of IBS symptoms.

FIG. 5 shows results of adequate relief of bloating symptoms.

FIG. 6 shows results of change from baseline in bloating symptoms aftertreatment with rifaximin.

DETAILED DESCRIPTION

Rifaximin (USAN, INN; see The Merck Index, XIII Ed., 8304, CAS No.80621-81-4), (2S,16Z,18E,20S,21S,22R,23R,24R,25S,26S,27S,28E)-5,6,21,23,25Pentahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca-(1,11,13)trienimino)benzofuro(4,5-e)pyrido(1,2,-a)benzimidazole-1,15(2H)-dione,25-acetate),is a semi-synthetic antibiotic produced from rifamycin O. Rifaximin is amolecule belonging to the rifamycin class of antibiotics, e.g., apyrido-imidazo rifamycin. Rifaximin exerts a broad antibacterialactivity, for example, in the gastrointestinal tract against localizedgastrointestinal bacteria that cause infectious diarrhea, irritablebowel syndrome, small intestinal bacterial overgrowth, Crohn's disease,and/or pancreatic insufficiency.

Rifaximin is also described in Italian Patent IT 1154655 and EP 0161534.EP patent 0161534 discloses a process for rifaximin production usingrifamycin O as the starting material (The Merck Index, XIII Ed., 8301).U.S. Pat. No. 7,045,620 B1 discloses polymorphic forms of rifaximin, asdo U.S. Ser. No. 11/658,702; U.S. Ser. No. 61/031,329; U.S. Ser. No.12/119,622; U.S. Ser. No. 12/119,630; U.S. Ser. No. 12/119,612; U.S.Ser. No. 12/119,600; U.S. Ser. No. 11/873,841; Publication WO2006/094662; and U.S. Ser. No. 12/393012. The applications and patentsreferred to here are incorporated herein by reference in their entiretyfor all purposes.

A rifamycin class antibiotic is, for example, a compound having thestructure of Formula I:

wherein A may be the structure A₁:

-   -   or the structure A₂

wherein, -x- is a covalent chemical bond or nil; R is hydrogen oracetyl;

R₁ and R₂ independently represent hydrogen, (C₁₋₄) alkyl, benzyloxy,mono- and di-(C₁₋₃)alkylamino-(C₁₋₄)alkyl, (C₁₋₃)alkoxy-(C₁₋₄)alkyl,hydroxymethyl, hydroxy-(C₂₋₄)-alkyl, nitro or R₁ and R₂ taken togetherwith two consecutive carbon atoms of the pyridine nucleus form a benzenering unsubstituted or substituted by one or two methyl or ethyl groups;R₃ is a hydrogen atom or nil; with the proviso that, when A is A₁, -x-is nil and R₃ is a hydrogen atom; with the further proviso that, when Ais A₂, -x- is a covalent chemical bond and R₃ is nil.

Also described herein is a compound as defined above, wherein A is A₁ orA₂ as above indicated, -x- is a covalent chemical bond or nil, R ishydrogen or acetyl, R₁ and R₂ independently represent hydrogen,(C₁₋₄)alkyl, benzyloxy, hydroxy-(C₂₋₄)alkyl,di-(C₁₋₃)alkylamino-(C₁₋₄)alkyl, nitro or R₁ and R₂ taken together withtwo consecutive carbon atoms of the pyridine nucleus form a benzene ringand R₃ is a hydrogen atom or nil; with the proviso that, when A is A₁,-x- is nil and R₃ is a hydrogen atom; with the further proviso that,when A is A₂, -x- is a covalent chemical bond and R₃ is nil.

Also described herein is a compound as defined above, wherein A is A₁ orA₂ as above indicated, -x- is a covalent chemical bond or nil, R isacetyl, R₁ and R₂ independently represent hydrogen, (C₁₋₄)alkyl or R₁and R₂ taken together with two consecutive carbon atoms of the pyridinenucleus form a benzene ring and R₃ is a hydrogen atom or nil; with theproviso that, when A is A₁, -x- is nil and R₃ is a hydrogen atom; withthe further proviso that, when A is A₂, -x- is a covalent chemical bondand R₃ is nil.

Also described herein is a compound as defined above, which is4-deoxy-4′-methyl-pyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV. Alsodescribed herein is a compound as defined above, which is 4-deoxy-pyrido[1′,2′:1,2]imidazo[5,4-c]rifamycin SV.

Also described herein is a compound as defined above, wherein A is asdescribed above, -x- is a covalent chemical bond or nil; R is hydrogenor acetyl; R₁ and R₂ independently represent hydrogen, (C₁₄)alkyl,benzyloxy, mono- and di-(C₁₋₃)alkylamino(C₁₄)alkyl,(C₁₋₃)alkoxy-(C₁₋₄)alkyl, hydroxymethyl, hydroxy-(C₂₋₄)-alkyl, nitro orR₁ and R₂ taken together with two consecutive carbon atoms of thepyridine nucleus form a benzene ring unsubstituted or substituted by oneor two methyl or ethyl groups; R₃ is a hydrogen atom or nil; with theproviso that, when A is A₁, -x- is nil and R₃ is a hydrogen atom; withthe further proviso that, when A is A₂, -x- is a covalent chemical bondand R₃ is nil.

Rifaximin is a compound having the structure of formula II:

In certain embodiments, the antibiotic comprises one or more of arifamycin, aminoglycoside, amphenicol, ansamycin, β-Lactam, carbapenem,cephalosporin, cephamycin, monobactam, oxacephem, lincosamide,macrolide, polypeptide, tetracycline, or a 2,4-diaminopyrimidine classantibiotic. Exemplary antibiotics of these classes are listed below.

Without wishing to be bound by any particular scientific theories,rifaximin acts by binding to the beta-subunit of the bacterialdeoxyribonucleic acid-dependent ribonucleic acid (RNA) polymerase,resulting in inhibition of bacterial RNA synthesis. It is active againstnumerous gram (+) and (−) bacteria, both aerobic and anaerobic. In vitrodata indicate rifaximin is active against species of Staphylococcus,Streptococcus, Enterococcus, and Enterobacteriaceae.

“Rifaximin”, as used herein, includes solvates and polymorphous forms ofthe molecule, including, for example, Form α, Form β, Form γ Form δ,Form ε, Form ζ, Form η, Form α-dry, Form ι, Form β-1, Form β-2, Formε-dry, mesylate Form or amorphous Forms of rifaximin. These forms aredescribed in more detail, for example, in U.S. Ser. No. 11/873,841; U.S.Ser. No. 11/658,702; EP 05 004 635.2, filed 3 May 2005; U.S. Pat. No.7,045,620; U.S. 61/031,329; and G. C. Viscomi, et al., CrystEngComm,2008, 10, 1074-1081 (April 2008). Each of these references is herebyincorporated by reference in entirety.

Medicinal preparations may contain gastrointestinal specific antibioticstogether with usual excipients, discussed infra.

“Polymorphism”, as used herein, refers to the occurrence of differentcrystalline forms of a single compound in distinct hydrate status, e.g.,a property of some compounds and complexes. Thus, polymorphs aredistinct solids sharing the same molecular formula, yet each polymorphmay have distinct physical properties. Therefore, a single compound maygive rise to a variety of polymorphic forms where each form hasdifferent and distinct physical properties, such as solubility profiles,melting point temperatures, hygroscopicity, particle shape, density,flowability, compatibility and/or x-ray diffraction peaks. Thesolubility of each polymorph may vary, thus, identifying the existenceof pharmaceutical polymorphs is essential for providing pharmaceuticalswith predictable solubility profiles. It is desirable to investigate allsolid state forms of a drug, including all polymorphic forms, and todetermine the stability, dissolution and flow properties of eachpolymorphic form. Polymorphic forms of a compound can be distinguishedin a laboratory by X-ray diffraction spectroscopy and by other methodssuch as, infrared spectrometry. For a general review of polymorphs andthe pharmaceutical applications of polymorphs see G. M. Wall, PharmManuf. 3, 33 (1986); J. K. Haleblian and W. McCrone, J Pharm. Sci., 58,911 (1969); and J. K. Haleblian, J. Pharm. Sci., 64, 1269 (1975), all ofwhich are incorporated herein by reference. As used herein, the termpolymorph is occasionally used as a general term in reference to theforms of rifaximin and include within the context, salt, hydrate,polymorph and amorphous forms of rifaximin disclosed herein. This usedepends on context and will be clear to one of skill in the art.

“GI specific antibiotic,” and “GI antibiotic” as used herein includeantibiotic known to have an effect on GI disease. For example, arifamycin class antibiotic (e.g., rifaximin), neomycin, metronidazole,teicoplanin, ciprofloxacin, doxycycline, tetracycline, augmentin,cephalexin, penicillin, ampicillin, kanamycin, rifamycin, vancomycin,and combinations thereof are useful GI specific antibiotics. Even morepreferable are GI specific antibiotics with low systemic absorption, forexample, rifaximin. Low systemic absorption includes, for example, lessthan 10% absorption, less than 5% absorption, less than 1% absorptionand less than 0.5% absorption. Low systemic absorption also includes,for example, from between about 0.01-1% absorption, from between about0.05-1% absorption, from between about 0.1-1% absorption, from betweenabout 1-10% absorption, or from between about 5-20% absorption.

“Ameliorate,” “amelioration,” “improvement” or the like refers to, forexample, a detectable improvement or a detectable change consistent withimprovement that occurs in a subject or in at least a minority ofsubjects, e.g., in at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%,50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 100% or in a range betweenabout any two of these values. Such improvement or change may beobserved in treated subjects as compared to subjects not treated withrifaximin, where the untreated subjects have, or are subject todeveloping, the same or similar disease, condition, symptom or the like.Amelioration of a disease, condition, symptom or assay parameter may bedetermined subjectively or objectively, e.g., self assessment by asubject(s), by a clinician's assessment or by conducting an appropriateassay or measurement, including, e.g., a quality of life assessment, aslowed progression of a disease(s) or condition(s), a reduced severityof a disease(s) or condition(s), or a suitable assay(s) for the level oractivity(ies) of a biomolecule(s), cell(s) or by detection of BDepisodes in a subject. Amelioration may be transient, prolonged orpermanent or it may be variable at relevant times during or after a GIspecific antibiotic is administered to a subject or is used in an assayor other method described herein or a cited reference, e.g., withintimeframes described infra, or about 1 hour after the administration oruse of a GI specific antibiotic to about 7 days, 2 weeks, 28 days, or 1,3, 6, 9 months or more after a subject(s) has received such treatment.

The “modulation” of, e.g., a symptom, level or biological activity of amolecule, or the like, refers, for example, that the symptom oractivity, or the like is detectably increased or decreased. Suchincrease or decrease may be observed in treated subjects as compared tosubjects not treated with a GI specific antibiotic, where the untreatedsubjects have, or are subject to developing, the same or similardisease, condition, symptom or the like. Such increases or decreases maybe at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%,75%, 80%, 85%, 90%, 95%, 98%, 100%, 150%, 200%, 250%, 300%, 400%, 500%,1000% or more or within any range between any two of these values.Modulation may be determined subjectively or objectively, e.g., by thesubject's self assessment, by a clinician's assessment or by conductingan appropriate assay or measurement, including, e.g., quality of lifeassessments or suitable assays for the level or activity of moleculeswithin a subject. Modulation may be transient, prolonged or permanent orit may be variable at relevant times during or after a GI specificantibiotic is administered to a subject or is used in an assay or othermethod described herein or a cited reference, e.g., within timesdescried infra, or about 1 hour of the administration or use of a GIspecific antibiotic to about 2 weeks, 28 days, 3, 6, 9 months or moreafter a subject(s) has received a GI specific antibiotic.

The term “modulate” may also refer to increases or decreases in theactivity of a cell in response to exposure to a GI specific antibiotic,e.g., the inhibition of proliferation and/or induction ofdifferentiation of at least a sub-population of cells in an animal suchthat a desired end result is achieved, e.g., a therapeutic result of GIspecific antibiotic used for treatment may increase or decrease over thecourse of a particular treatment.

The language “a prophylactically effective amount” of a compound refersto an amount of a compound of the invention of formula I, formula II, orotherwise described herein which is effective, upon single or multipledose administration to the subject, in preventing or treating BD.

As used herein, “subject” includes organisms which are capable ofsuffering from a bowel disease or other disorder treatable by arifamycin class antibiotic (e.g., rifaximin) or who could otherwisebenefit from the administration of a rifamycin class antibiotic (e.g.,rifaximin) as described herein, such as human and non-human animals.Preferred human animals include human subjects. The term “non-humananimals” of the invention includes all vertebrates, e.g., mammals, e.g.,rodents, e.g., mice, and non-mammals, such as non-human primates, e.g.,sheep, dog, cow, chickens, amphibians, reptiles, etc. Susceptible to abowel disorder is meant to include a subject at risk of developing abowel disorder or a person who is in remission from a BD or a person whomay relapse from a BD, e.g., a subject suffering from immunesuppression, a subject that has been exposed to a bacterial infection,physicians, nurses, a subject traveling to remote areas known to harborbacteria that cause travelers' diarrhea, a family history of BD, anaging person, a person with liver damage, a subject in IBS remission, asubject who has had HE episodes in the past, a person with mind HE, asubject with uncontrollable diarrhea, a subject with dIBS, etc.

The language “a prophylactically effective amount” of a compound refersto an amount of a compound of the invention of formula I, formula II, orotherwise described herein which is effective, upon single or multipledose administration to the subject, in preventing or treating BD.

The term “administration” or “administering” includes routes ofintroducing a GI specific antibiotic to a subject to perform theirintended function. Examples of routes of administration that may be usedinclude injection, oral, inhalation, vaginal, rectal and transdermal.The pharmaceutical preparations may be given by forms suitable for eachadministration route. For example, these preparations are administeredin tablets or capsule form, by injection, inhalation, eye lotion, eyedrops, ointment, suppository, etc. administration by injection, infusionor inhalation; topical by lotion or ointment; and rectal bysuppositories. Oral administration is preferred. The injection can bebolus or can be continuous infusion. Depending on the route ofadministration, a GI specific antibiotic can be coated with or disposedin a selected material to protect it from natural conditions that maydetrimentally effect its ability to perform its intended function. A GIspecific antibiotic can be administered alone, or in conjunction witheither another agent or agents as described above or with apharmaceutically-acceptable carrier, or both. A GI specific antibioticcan be administered prior to the administration of the other agent,simultaneously with the agent, or after the administration of the agent.Furthermore, a GI specific antibiotic can also be administered in aproform, which is converted into its active metabolite, or more activemetabolite in vivo.

Administration “in combination with” one or more further therapeuticagents includes simultaneous (concurrent) and consecutive administrationin any order.

As will be readily apparent to one skilled in the art, the useful invivo dosage to be administered and the particular mode of administrationwill vary depending upon the age, weight and mammalian species treated,the particular compounds employed, and/or the specific use for whichthese compounds are employed. The determination of effective dosagelevels, that is the dosage levels necessary to achieve the desiredresult, can be accomplished by one skilled in the art using routinepharmacological methods. Typically, human clinical applications ofproducts are commenced at lower dosage levels, with dosage level beingincreased until the desired effect is achieved.

The term “obtaining” as in “obtaining a GI specific antibiotic” isintended to include purchasing, synthesizing or otherwise acquiring a GIspecific antibiotic.

The language “a prophylactically effective amount” of a compound refersto an amount of a GI specific antibiotic which is effective, upon singleor multiple dose administration to the subject, in preventing ortreating BD, e.g., IBS.

The term “pharmaceutical agent composition” (or agent or drug) as usedherein refers to a chemical compound, composition, agent or drug capableof inducing a desired therapeutic effect when properly administered to apatient. It does not necessarily require more than one type ofingredient.

As used herein, “durability of response” includes for example, adequaterelief of symptoms after removal of treatment, continuous adequaterelief of symptoms after removal of treatment, or response that isgreater than or superior to placebo response. A response by a subjectmay be considered durable, for example, if they have a response to therifamycin class antibiotic after removal from treatment. The duration ofresponse, may be, for example, 2 days, 7 days, two weeks, 3 weeks, 4weeks, 12 weeks, between about 1 week and about 24 weeks or longer. Theresponse may be measured, for example using one or more of the methodsoutlined below, including, for example, a subject's subjectiveassessment of their symptoms or a healthcare provider's or caretaker'sassessment of a subject's symptoms.

As used herein, “selecting subject's who respond,” “selection ofsubject's who respond” or the like, include, for example, determiningthat a subject has responded to treatment based on a decrease of BDsymptoms and/or following label instructions to administer a product(e.g., a rifamycin class antibiotic) for a certain period of time or thelike. The determination or selection may be based on the label (e.g.,package or package insert) instructions or on the a subject's subjectiveassessment of their symptoms or a healthcare provider's or caretaker'sassessment of a subject's symptoms.

Methods of Treatment

Provided herein are methods of treating, preventing, or alleviatingbowel related disorders comprising administering to a subject in needthereof an effective amount of a rifamycin class antibiotic (e.g.,rifaximin). Bowel related disorders (e.g., bowel diseases) include oneor more of irritable bowel syndrome (IBS), uncontrolleddiarrhea-associated Irritable Bowel Syndrome (dIBS), Crohn's disease,traveler's diarrhea, ulcerative colitis, enteritis, small intestinalbacterial overgrowth, chronic pancreatitis, pancreatic insufficiency,colitis, diverticular disease, hepatic encephalopathy, and/or pouchitis.

Table 1 below demonstrates that men respond differentially to treatmentwith rifaximin. Table 2 demonstrates response to the treatment iscorrelated with the duration of disease.

TABLE 1 Treatment effect Thresholds (IBS Sx, Bloating) Gender M versus. 21%*, 13.6% F 3.5%, 3.9% Age <65 versus. 6.9%, 6.8% ≧65 19.1%, 3.2% dIBS Type dIBS only versus. 6.3%, 4.5% aIBS 31.4%*, 31.4%  *p-value <0.05

TABLE 2 Treatment effect Thresholds (IBS Sx, Bloating) Diabetes HistoryY versus. −12.7%, −5.6%  N 9.5%, 7.4% Disease Duration: ≦10 y 1.8%, 2.8%10-20 y 20.1%, 11.7% >20 y 46.6%*, 35.1%  *p-value < 0.05

It was surprisingly shown that a rifamycin class antibiotic (e.g.,rifaximin) is particularly efficacious in men and in subjects with longduration of disease.

Durability of Response

Embodiments of the invention relate to the discovery that the dosingregimes described herein of rifaximin results in a durability ofresponse and amelioration of BD symptoms in subjects in need thereof.One embodiment of the invention is a method of treating bowel disease(BD) with a durability of antibiotic response, by administering atherapeutically effective amount of a rifamycin class antibiotic to asubject in need thereof, selecting subjects who respond to treatmentafter being treated for between about 1 and about 24 weeks, and removinga responding subject from treatment wherein after removal of treatmentthere is a durability of response. The selecting may be by a healthcareprofessional, by self selection or by selection of one in a position todecide or discern symptoms or to diagnose a response to the antibiotic.Removal of treatment comprises, for example, ceasing to administer,ceasing to recommend administration of the antibiotic, and/or advisingresponding subjects to stop taking the antibiotic.

In one embodiment, the recommendation (e.g., selection) is made on alabel of a pharmaceutical product, which indicates that the productshould be administered for 14 days (e.g., two weeks). For example, asubject in need of treatment is administered rifaximin 550 mg TID fortwo weeks and instructed by a label. In one embodiment, therecommendation (e.g., selection) is made on a label of a pharmaceuticalproduct, which indicates that the product should be administered for twoweeks. For example, a subject in need of treatment is administeredrifaximin 550 mg BID for two weeks as instructed by a label. In oneembodiment, selecting is following dosing instructions on a packageinsert of a pharmaceutical product.

Also described herein are methods for maintenance of remission of boweldisease in a subject comprising administering a therapeuticallyeffective amount of rifaximin for at least 25 weeks to a subject in needthereof.

Yet another aspect of this invention relates to a method of treating asubject (e.g., mammal, human, horse, dog, cat) with rifaximin who is inneed thereof. Identifying a subject in need of such treatment can be inthe judgment of a subject or a health care professional and can besubjective (e.g., opinion) or objective (e.g., measurable by a test ordiagnostic method). Rifaximin may be used in various treatment regimes.These regimes may vary depending upon the subject and the type oftreatment.

Rifaximin may be administered, for example, twice a day, three times aday, or four times or more often as necessary per day. Rifaximin may beadministered in doses, for example of from about between 25 mg BID toabout 3000 mg TID. Another example is administering rifaximin frombetween about 4.0 g/day to about 7.25 g/day. The rifaximin may beadministered, for example, in tablet form, powered form, liquid for orin capsules.

Subjects in need thereof include subjects having or that are susceptibleto BD, are in remission from BD, males and/or older subjects with longduration of disease, as disclosed further below.

As used herein, a therapeutically effective amount means an amounteffective, when administered to a human or non-human subject, to providea therapeutic benefit such as an amelioration of symptoms, e.g., anamount effective to decrease the symptoms of BDs, or maintenance ofremission of a BD.

In certain embodiments, the rifaximin is administered to a subject frombetween about 1 week to about 6 weeks in duration, from between about 8weeks to about 12 weeks in duration, or from between 1 day to about 7days. The rifaximin may be administered from between about 1 day andabout 1 year, or from 1 week to about 24 weeks. The rifaximin may beadministered, for example, for the remainder of a subject's life. Therifaximin may be administered intermittently or continuously during thecourse of treatment. Length of treatment may vary depending on the typeand length of disease and the proper length of treatment may be easilydetermined by one of skill in the art having the benefit of thisdisclosure.

For any of the embodiments, rifaximin may be administered, for example,once daily, twice daily, three times daily, or four times daily (or moreoften as necessary for a particular subject) to a subject. In somemethods of the present invention comprise administering the rifaximinonce daily to the subject because it may, for example, minimize the sideeffects and increase patient compliance. Also preferred, are twice andthree times daily administration of rifaximin.

Dosages, according to certain preferred embodiments, range from betweenabout 50 to about 6000 mg of rifaximin administered daily. For example,a dose of 550 mg may be administered to a subject twice daily. Otherappropriate dosages for methods according to this invention may bedetermined by health care professionals or by the subject. The amount ofrifaximin administered daily may be increased or decreased based on theweight, age, health, sex or medical condition of the subject. One ofskill in the art would be able to determine the proper dose for asubject based on this disclosure.

According to certain embodiments, rifaximin may be administered incombination with other compounds, including for example,chemotherapeutic agents, anti-inflammatory agents, anti-pyretic agentsradiosensitizing agents, radioprotective agents, urologic agents,anti-emetic agents, and/or anti-diarrheal agents, for example,cisplatin, carboplatin, docetaxel, paclitaxel, flurouracil,capecitabine, gemcitabine, irinotecan, topotecan, etoposide, mitomycin,gefitinib, vincristine, vinblastine, doxorubicin, cyclophosphamide,celecoxib, rofecoxib, valdecoxib, ibuprofen, naproxen, ketoprofen,dexamethasone, prednisone, prednisolone, hydrocortisone, acetaminophen,misonidazole, amifostine, tamsulosin, phenazopyridine, ondansetron,granisetron, alosetron, palonosetron, promethazine, prochlorperazine,trimethobenzamide, aprepitant, diphenoxylate with atropine, and/orloperamide.

Risk Selection Methods

The methods described herein may also further comprise geneticallyprofiling for genetic risk of BD and selecting to treat an at risksubject. For example, an at-risk subject may be determined to be at riskof a bowel disease by genetic screening, family history, lifestyle,travel plans and the like. Genetic screening may, for example, be forgenes and expression profiles or epigenetic modifiers shown to affect orpredict bowel disease or susceptibility for bowel diseases. Mutationswhich may be screened for include mutations or polymorphisms in, forexample, Nod2, CFTR, or CARD15. Nod2, a gene involved in the immunesystems initial response to bacterial infection, significantly increasesthe risk of Crohn's disease. The CFTR protein resides in the surface ofcells lining the digestive system, lungs and sweat glands. In normalcells, it acts as an ion channel that transports chloride into and outof cells. It also controls the regulation of other transport pathwaysregulating the passage of fluid and bicarbonate across cell membranes.DNA sequence variations (or mutations) alone do not explain CFTR-relatedgastrointestinal disease patterns; rather, epigenetic modifiers, orchanges that leave the gene's sequence of DNA intact, influence CFTRexpression.

For example, a subject may be typed for rs6822844 and/or rs2305767 toindicate risk of celiac disease. One study examined 778 individuals withceliac disease and 1,422 healthy controls. The authors found that each Tat rs6822844 lowered subjects' risk of celiac disease by about 1.6times. See Thernakova A et al. (2007) “Novel association in chromosome4q27 region with rheumatoid arthritis and confirmation of type 1diabetes point to a general risk locus for autoimmune diseases.” Am JHum Genet 81(6):1284-8; and van Heel DA et al. (2007) “A genome-wideassociation study for celiac disease identifies risk variants in theregion harboring IL2 and IL21.” Nat Genet 39(7):827-9. Another studyexamined 463 individuals with celiac disease and 686 healthy controls.The authors found that people with a C at both copies had 2.3 timeslower odds for celiac disease than those with the TT genotype. See HuntK A et al. (2006) “Lack of association of MYO9B genetic variants withcoeliac disease in a British cohort.” Gut 55(7):969-72; Núñez C et al.(2006) “No evidence of association of the MYO9B polymorphisms withceliac disease in the Spanish population.” Tissue Antigens 68(6):489-92;Cirillo G et al. (2007) “Do MYO9B genetic variants predispose to coeliacdisease? An association study in a cohort of South Italian children.”Dig Liver Dis 39(3):228-31; Cirillo G et al. (2007) “Do MYO9B geneticvariants predispose to coeliac disease? An association study in a cohortof South Italian children.” Dig Liver Dis 39(3):228-31; Cirillo G et al.(2007) “Do MYO9B genetic variants predispose to coeliac disease? Anassociation study in a cohort of South Italian children.” Dig Liver Dis39(3):228-31.

For example, a subject may be typed for 8q24 region; Marker:rs6983267 todetermine risk for colon cancer. This SNP occurs in a hypothetical genecalled LOC727677. It has been suggested that the riskier version of thisSNP is associated not only with an increased risk of colorectal cancer,but also with formation of the precancerous adenomatous polyps. Theriskier version of this SNP has also been linked to prostate cancer insome studies, though more research is needed to confirm thisassociation. See Haiman et al. (2007) “A common genetic risk factorcolorectal and prostate cancer.” Nat Genet 39(8):954-6; and Tomlinson etal. (2007) “A genome-wide association scan of tag SNPs identifies asusceptibility variant for colorectal cancer at 8q24.21.” Nat Genet39(8):984-988; and Zanke et al. (2007) “Genome-wide association scanidentifies a colorectal cancer susceptibility locus on chromosome 8q24.”Nat Genet 39(8):989-994.

For example, a subject may be typed for NOD2(1) SNP: rs2066844; NOD2(2)SNP: rs2066845; NOD2(3) SNP: rs2066847; IL23R(1) SNP: rs11209026; NKX2-3SNP: rs11190140; 5p13 region SNP: rs17234657; PTPN2 SNP: rs1893217; MST1SNP: rs3197999; : IRGM SNP: rs7714584; IL23R(2) SNP: rs11805303; and/or10q21 region SNP: rs10761659 to determine risk of Crohn's disease. SeeHugot et al. (2001) “Association of NOD2 leucine-rich repeat variantswith susceptibility to Crohn's disease.” Nature 411(6837):599-603; Oguraet al. (2001) “A frameshift mutation in NOD2 associated withsusceptibility to Crohn's disease.” Nature 411(6837):603-6; Rioux et al.(2007) “Genome-wide association study identifies new susceptibility locifor Crohn disease and implicates autophagy in disease pathogenesis.” NatGenet 39(5):596-604; Libioulle et al. (2007) “Novel Crohn's diseaselocus identified by genome-wide association maps to a gene desert on5p13.1 and modulates expression of PTGER4.” PLoS Genet 3(4):e58; Hampeet al. (2007) “A genome-wide association scan of non-synonymous SNPsidentifies a susceptibility variant for Crohn disease in ATG16L1.” NatGenet 39(2):207-11; Duerr et al. (2006) “A genome-wide association studyidentifies IL23R as an inflammatory bowel disease gene.” Science314(5804):1461-1463; van Limbergen et al. (2007) “IL23R Arg381Gln isassociated with childhood onset inflammatory bowel disease in Scotland.”Gut 56(8):1173-4; Wellcome Trust Case Control Consortium (2007)“Genome-wide association study of 14,000 cases of seven common diseasesand 3,000 shared controls.” Nature 447(7145):661-78; Parkes et al.(2007) “Sequence variants in the autophagy gene IRGM and multiple otherreplicating loci contribute to Crohn's disease susceptibility.” NatGenet 39(7):830-2; Sheibanie et al. (2007) “The proinflammatory effectof prostaglandin E2 in experimental inflammatory bowel disease ismediated through the IL-23→IL-17 axis.” J Immunol 178(12):8138-47;Simoncic et al. (2007) “The T cell protein tyrosine phosphatase is anegative regulator of janus family kinases 1 and 3.” Curr Biol12(6):446-53; You-Ten et al. (1997) “Impaired bone marrowmicroenvironment and immune function in T cell protein tyrosinephosphatase-deficient mice.” J Exp Med 22(16):5662-8; Barrett et al.(2008) “Genome-wide association defines more than 30 distinctsusceptibility loci for Crohn's disease.” Nat Genet 40(8):955-62;Goyette er al. (2008) “Gene-centric association mapping of chromosome 3pimplicates MST1 in IBD pathogenesis” Mucosal Immunology 1:131-138;Barrett et al. (2008). “Genome-wide association defines more than 30distinct susceptibility loci for Crohn's disease.” Nat Genet40(8):955-62; McCarroll et al (2008) “Deletion polymorphism upstream ofIRGM associated with altered IRGM expression and Crohn's disease.” NatGenet 40(9):1107-1112; and Singh et al. (2006) “Human IRGM inducesautophagy to eliminate intracellular mycobacteria.” Science313(5792):1438-41.

Pharmaceutical Preparations

The invention also provides pharmaceutical compositions, comprising aneffective amount of a rifamycin class antibiotic ((e.g., rifaximin or arifaximin polymorph) described herein and a pharmaceutically acceptablecarrier. In a further embodiment, the effective amount is effective totreat a bacterial infection, e.g., small intestinal bacterialovergrowth, Crohn's disease, hepatic encephalopathy, antibioticassociated colitis, and/or diverticular disease.

For examples of the use of rifaximin and formulations thereof to treatTravelers' diarrhea, see Infante R M, Ericsson C D, Zhi-Dong J, Ke S,Steffen R, Riopel L, Sack D A, DuPont, H L. EnteroaggregativeEscherichia coli Diarrhea in Travelers: Response to Rifaximin Therapy.Clinical Gastroenterology and Hepatology. 2004; 2:135-138; and SteffenR, M.D., Sack D A, M.D., Riopel L, Ph.D., Zhi-Dong J, Ph.D., SturchlerM, M.D., Ericsson C D, M.D., Lowe B, M.Phil., Waiyaki P, Ph.D., White M,Ph.D., DuPont H L, M.D. Therapy of Travelers' Diarrhea With Rifaximin onVarious Continents. The American Journal of Gastroenterology. May 2003,Volume 98, Number 5, all of which are incorporated herein by referencein their entirety.

One embodiment pharmaceutical compositions comprising rifaximin or anypolymorphic form thereof and a pharmaceutically acceptable carrier. Thatis, formulations may contain only one polymorph or may contain a mixtureof more than one polymorph. Polymorph, in this context, refers to anyphysical form, hydrate, acid, salt or the like of rifaximin. Mixturesmay be selected, for example on the basis of desired amounts of systemicadsorption, dissolution profile, desired location in the digestive tractto be treated, and the like. The pharmaceutical composition furthercomprises excipients, for example, one or more of a diluting agent,binding agent, lubricating agent, disintegrating agent, coloring agent,flavoring agent or sweetening agent. Compositions may be formulated forselected coated and uncoated tablets, hard and soft gelatin capsules,sugar-coated pills, lozenges, wafer sheets, pellets and powders insealed packet. For example, compositions may be formulated for topicaluse, for example, ointments, pomades, creams, gels and lotions.

In an embodiment, the rifamycin class antibiotic (e.g., rifaximin) isadministered to the subject using a pharmaceutically-acceptableformulation, e.g., a pharmaceutically-acceptable formulation thatprovides sustained delivery of the rifamycin class antibiotic (e.g.,rifaximin) to a subject for at least 12 hours, 24 hours, 36 hours, 48hours, one week, two weeks, three weeks, or four weeks after thepharmaceutically-acceptable formulation is administered to the subject.

In certain embodiments, these pharmaceutical compositions are suitablefor topical or oral administration to a subject. In other embodiments,as described in detail below, the pharmaceutical compositions of thepresent invention may be specially formulated for administration insolid or liquid form, including those adapted for the following: (1)oral administration, for example, drenches (aqueous or non-aqueoussolutions or suspensions), tablets, boluses, powders, granules, pastes;(2) parenteral administration, for example, by subcutaneous,intramuscular or intravenous injection as, for example, a sterilesolution or suspension; (3) topical application, for example, as acream, ointment or spray applied to the skin; (4) intravaginally orintrarectally, for example, as a pessary, cream or foam; or (5) aerosol,for example, as an aqueous aerosol, liposomal preparation or solidparticles containing the compound.

The phrase “pharmaceutically acceptable” refers to those rifamycin classantibiotic (e.g., rifaximin) described herein, compositions containingsuch compounds, and/or dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of humanbeings and animals without excessive toxicity, irritation, allergicresponse, or other problem or complication, commensurate with areasonable benefit/risk ratio.

The phrase “pharmaceutically-acceptable carrier” includespharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial, involved in carrying or transporting the subject chemical fromone organ, or portion of the body, to another organ, or portion of thebody. Each carrier must be “acceptable” in the sense of being compatiblewith the other ingredients of the formulation and not injurious to thepatient. Some examples of materials which can serve aspharmaceutically-acceptable carriers include: (1) sugars, such aslactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21)other non-toxic compatible substances employed in pharmaceuticalformulations.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically-acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Compositions containing a rifamycin class antibiotic (e.g., rifaximin)include those suitable for oral, nasal, topical (including buccal andsublingual), rectal, vaginal, aerosol and/or parenteral administration.The compositions may conveniently be presented in unit dosage form andmay be prepared by any methods well known in the art of pharmacy. Theamount of active ingredient which can be combined with a carriermaterial to produce a single dosage form will vary depending upon thehost being treated, the particular mode of administration. The amount ofactive ingredient which can be combined with a carrier material toproduce a single dosage form will generally be that amount of thecompound which produces a therapeutic effect. Generally, out of onehundred percent, this amount will range from about 1% to about 99% ofactive ingredient, preferably from about 5% to about 70%, mostpreferably from about 10% to about 30%.

Liquid dosage forms for oral or rectal administration of the rifamycinclass antibiotic (e.g., rifaximin) include pharmaceutically-acceptableemulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to the active ingredient, the liquid dosage forms maycontain inert diluents commonly used in the art, such as, for example,water or other solvents, solubilizing agents and emulsifiers, such asethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils(in particular, cottonseed, groundnut, corn, germ, olive, castor andsesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycolsand fatty acid esters of sorbitan, and mixtures thereof.

In addition to inert diluents, the oral compositions can includeadjuvants such as wetting agents, emulsifying and suspending agents,sweetening, flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active rifamycin class antibiotic (e.g.,rifaximin) may contain suspending agents as, for example, ethoxylatedisostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agarand tragacanth, and mixtures thereof.

Pharmaceutical compositions of the invention for rectal or vaginaladministration may be presented as a suppository, which may be preparedby mixing one or more rifamycin class antibiotic (e.g., rifaximin) withone or more suitable nonirritating excipients or carriers comprising,for example, cocoa butter, polyethylene glycol, a suppository wax or asalicylate, and which is solid at room temperature, but liquid at bodytemperature and, therefore, will melt in the rectum or vaginal cavityand release the active agent. Compositions which are suitable forvaginal administration can include pessaries, tampons, creams, gels,pastes, foams or spray formulations containing such carriers as areknown in the art to be appropriate.

Dosage forms for the topical or transdermal administration of arifamycin class antibiotic (e.g., rifaximin) can include powders,sprays, ointments, pastes, creams, lotions, gels, solutions, patches andinhalants. The active rifamycin class antibiotic (e.g., rifaximin) maybe mixed under sterile conditions with a pharmaceutically-acceptablecarrier, and with any preservatives, buffers, or propellants which maybe required.

The ointments, pastes, creams and gels may contain, in addition torifamycin class antibiotic (e.g., rifaximin), excipients, such as animaland vegetable fats, oils, waxes, paraffins, starch, tragacanth,cellulose derivatives, polyethylene glycols, silicones, bentonites,silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a rifamycin classantibiotic (e.g., rifaximin), excipients such as lactose, talc, silicicacid, aluminum hydroxide, calcium silicates and polyamide powder, ormixtures of these substances. Sprays can additionally contain customarypropellants, such as chlorofluorohydrocarbons and volatile unsubstitutedhydrocarbons, such as butane and propane.

The rifamycin class antibiotic (e.g., rifaximin) can be alternativelyadministered by aerosol. This is accomplished, for example, by preparingan aqueous aerosol, liposomal preparation or solid particles containingthe compound. A non-aqueous (e.g., fluorocarbon propellant) suspensioncould be used. Sonic nebulizers are preferred because they minimizeexposing the agent to shear, which can result in degradation of thecompound.

Examples of suitable aqueous and non-aqueous carriers which may beemployed in the pharmaceutical compositions can include water, ethanol,polyols (such as glycerol, propylene glycol, polyethylene glycol, andthe like), and suitable mixtures thereof, vegetable oils, such as oliveoil, and injectable organic esters, such as ethyl oleate. Properfluidity can be maintained, for example, by the use of coatingmaterials, such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents which delay absorption such as aluminum monostearate andgelatin.

In some cases, to prolong the effect of a drug, it is desirable to alterthe absorption of the drug. This may be accomplished by the use of aliquid suspension of crystalline, salt or amorphous material having poorwater solubility. The rate of absorption of the drug may then depend onits rate of dissolution which, in turn, may depend on crystal size andcrystalline form. Alternatively, delayed absorption of a drug form isaccomplished by dissolving or suspending the drug in an oil vehicle.

When the rifamycin class antibiotic (e.g., rifaximin) are administeredas pharmaceuticals, to humans and animals, they can be given per se oras a pharmaceutical composition containing, for example, 0.1 to 99.5%(more preferably, 0.5 to 90%) of active ingredient in combination with apharmaceutically-acceptable carrier.

Regardless of the route of administration selected, the rifamycin classantibiotic (e.g., rifaximin), which may be used in a suitable hydratedform, and/or the pharmaceutical compositions of the present invention,are formulated into pharmaceutically-acceptable dosage forms byconventional methods known to those of skill in the art.

Actual dosage levels and time course of administration of the activeingredients in the pharmaceutical compositions of the invention may bevaried so as to obtain an amount of the active ingredient which iseffective to achieve the desired therapeutic response for a particularpatient, composition, and mode of administration, without being toxic tothe patient. An exemplary dose range is from 25 to 3000 mg per day.

In combination therapy treatment, both the compounds of this inventionand the other drug agent(s) are administered to mammals (e.g., humans,male or female) by conventional methods. The agents may be administeredin a single dosage form or in separate dosage forms. Effective amountsof the other therapeutic agents are well known to those skilled in theart. However, it is well within the skilled artisan's purview todetermine the other therapeutic agent's optimal effective-amount range.In one embodiment of the invention in which another therapeutic agent isadministered to an animal, the effective amount of the compound of thisinvention is less than its effective amount in case the othertherapeutic agent is not administered. In another embodiment, theeffective amount of the conventional agent is less than its effectiveamount in case the compound of this invention is not administered. Inthis way, undesired side effects associated with high doses of eitheragent may be minimized. Other potential advantages (including withoutlimitation improved dosing regimens and/or reduced drug cost) will beapparent to those skilled in the art.

In various embodiments, the therapies (e.g., prophylactic or therapeuticagents) are administered less than 5 minutes apart, less than 30 minutesapart, 1 hour apart, at about 1 hour apart, at about 1 to about 2 hoursapart, at about 2 hours to about 3 hours apart, at about 3 hours toabout 4 hours apart, at about 4 hours to about 5 hours apart, at about 5hours to about 6 hours apart, at about 6 hours to about 7 hours apart,at about 7 hours to about 8 hours apart, at about 8 hours to about 9hours apart, at about 9 hours to about 10 hours apart, at about 10 hoursto about 11 hours apart, at about 11 hours to about 12 hours apart, atabout 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hoursto 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hoursapart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hoursto 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hourspart. In preferred embodiments, two or more therapies are administeredwithin the same patient's visit.

In certain embodiments, one or more of the rifamycin class antibiotic(e.g., rifaximin) and one or more other therapies (e.g., prophylactic ortherapeutic agents) are cyclically administered. Cycling therapyinvolves the administration of a first therapy (e.g., a firstprophylactic or therapeutic agent) for a period of time, followed by theadministration of a second therapy (e.g., a second prophylactic ortherapeutic agent) for a period of time, optionally, followed by theadministration of a third therapy (e.g., prophylactic or therapeuticagent) for a period of time and so forth, and repeating this sequentialadministration, i.e., the cycle in order to reduce the development ofresistance to one of the therapies, to avoid or reduce the side effectsof one of the therapies, and/or to improve the efficacy of thetherapies.

In certain embodiments, the administration of the same compounds may berepeated and the administrations may be separated by at least about 1day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 3weeks, 4 weeks, 5 weeks, 6 weeks, 12 weeks, 2 months, 75 days, 3 months,or at least 6 months. In other embodiments, the administration of thesame therapy (e.g., prophylactic or therapeutic agent) other than arifamycin class antibiotic (e.g., rifaximin) may be repeated and theadministration may be separated by at least at least 1 day, 2 days, 3days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3months, or at least 6 months. In one embodiment, a label on a rifamycinclass antibiotic may instruct, for example, do not repeat more oftenthan every 6 weeks. In another embodiment, a label on a rifamycin classantibiotic may instruct, for example, do not repeat more often thanevery 3 weeks. In another embodiment, a label on a rifamycin classantibiotic may instruct, for example, do not repeat more often thanevery 3-12 weeks. Included within ranges given herein for dosage oradministration are any value within the range.

In certain embodiments, retreatment is efficacious in combination withthe methods disclosed herein. See for example, Rifaximin versus OtherAntibiotics in the Primary Treatment and Retreatment of BacterialOvergrowth in IBS, Janet Yang, Hyo-Rang Lee, Kimberly Low, SoumyaChatterjee, and Mark Pimentel, Dig Dis Sci (2008) 53:169-174. Forexample, methods as described herein may further comprise determiningsymptom relief in a subject and administering a second course ofrifaximin treatment if symptoms remain unresolved. Methods may alsofurther comprise, for example, determining the gender of a subject andadministering the therapeutically effective amount to a male subject.

Certain indications may require longer treatment times. For example,travelers' diarrhea treatment may only last from between about 12 hoursto about 72 hours, while a treatment for Crohn's disease may be frombetween about 1 day to about 3 months and a treatment for hepaticencephalopathy may be from between 1 day and 12 months. For example, HEmay require chronic therapy for the remainder of a subject's life.Crohn's disease subjects may also require chronic therapy.

Kits

Kits are also provided herein, for example, kits for treating a boweldisorder in a subject treating bowel disease (BD) with a durability ofantibiotic response; methods of treating bowel disease (BD) in males;methods of treating bloating due to BD in males; methods of treating BDin older subjects; methods of treating BD in older subjects with longduration of disease; and/or methods of predicting response to rifaximintreatment for BD. The kits may contain, for example, a polymorph oramorphous form of rifaximin and instructions for use. The instructionsfor use may contain proscribing information, dosage information, storageinformation, and the like.

In one embodiment, the label describes adverse events comprising one ormore of infections and infestations, gastrointestinal disorders, nervoussystem disorders, and musculoskeletal and connective tissue disorders.

In one embodiment, the label describes a length of treatment with therifamycin class antibiotic, whereby a subject is selected as respondingto treatment if a healthcare professional prescribes the rifamycin classantibiotic according to the label instructions.

In one embodiment, the label describes a length of treatment with therifamycin class antibiotic, whereby a subject is removed from treatmentif a healthcare professional prescribes the rifamycin class antibioticaccording to the label instructions.

Label instructions, include, for example, instructions to take therifamycin class antibiotic for 14 days for the treatment of dIBS. Theinstructions could also read, for example, take for 1650 mg/day ofrifaximin for 14 days for acute treatment for symptomaticdiarrhea-associated Irritable Bowel Syndrome (dIBS).

Packaged compositions are also provided, and may comprise atherapeutically effective amount of one or more of a one or more of anamorphous form, Form α, Form β, Form γ, Form δ, Form ε, Form ζ, or Formη polymorph of rifaximin of rifaximin and a pharmaceutically acceptablecarrier or diluent, wherein the composition is formulated for treating asubject suffering from or susceptible to a bowel disorder, and packagedwith instructions to treat a subject suffering from or susceptible to abowel disorder.

EXAMPLES

It should be appreciated that the invention should not be construed tobe limited to the example, which is now described; rather, the inventionshould be construed to include any and all applications provided hereinand all equivalent variations within the skill of the ordinary artisan.

Example 1

This example relates to a study of rifaximin in subjects with dIBS.Subjects received daily one of BID doses of placebo, rifaximin 275 mg,550 mg, or 1100 mg for 14 days. A fifth group of subjects receivedrifaximin 550 mg BID for a period of 28 days. There were two measures ofefficacy assessed. Subjects were questioned on the relief of overall IBSsymptoms and bloating. Adequate relief of IBS related symptoms (SGA) andIBS-related bloating (IBS-B) were assessed, and a dose of 550 mg BID for2 weeks demonstrated statistically significant relief. The analysesdefined success as a “yes” response to questions regarding adequaterelief.

Predictors of response analyses showed that the response was similaracross some subgroups however, there were differences. Analyses onpredictors of response demonstrated that age (older subjects and thosewith a longer IBS duration); sex (males) and baseline severity (mild tomoderate symptoms) were predictors of response. All subpopulations inthe study responded to therapy. Baseline severity was determined using7-point Lickert scales during screening for Abdominal Pain/Discomfortand Bloating, and the number, type (normal, hard, loose) and urgency ofbowel movements.

Duration of effect was assessed in a follow-up period. Subjects thatresponded in the 4 week treatment period were followed for an additional3 months. The subjects in the placebo group had a greater rate ofdecline in response than the 550 mg BID 2 week group, demonstrating thatsubjects treated with rifaximin had a better chance of maintainingsymptom relief than their placebo treated counterparts.

Percentage of Subjects with Adequate Relief of IBS and Bloating Symptoms

The effect of treatment on the percentage of subjects who reportedadequate relief of IBS and bloating symptoms for at least two of thefinal three weeks during the treatment phase (Weeks 1 to 4) is shown inTables 3-5 and FIGS. 4-6 below.

During the treatment phase, 52.4% of subjects on RFX 550 mg BID met theIBS symptoms responder criterion, compared with 44.2% of the placebosubjects (odds ratio of 1.6 and p value=0.0314). Similarly, 46.1% ofsubjects in the 550 mg BID group met the bloating symptom respondercriterion, compared with 39.6% of the placebo group (odds ratio of 1.6and p value=0.0402).

TABLE 3 Percentage of Subjects with Adequate Relief of IBS and BloatingSymptoms - ITT Population RFX 550 Odds Ratio Placebo mg BID EstimateMeasure [N = 197] [N = 191] (95% CI) P-Value IBS 44.2% 52.4% 1.60 0.0314Symptoms (1.04, 2.45) Bloating 39.6% 46.1% 1.58 0.0402 Symptom (1.02,2.45)

TABLE 4 Percentage of Subjects with Number of Weeks with Adequate Reliefof IBS Symptoms - ITT Population Number of RFX 550 Weeks - IBS Placebomg BID Odds Ratio Symptoms [N = 197] [N = 191] Estimate P-Value 1.540.0216 (1.07, 2.24) 0 45% 33% 1  7% 11% 2 15% 15% 3 16% 23% 4 15% 16%

TABLE 5 Percentage of Subjects with Number of Weeks with Adequate Reliefof Bloating Symptoms - ITT Population Number of RFX 550 Weeks - BloatingPlacebo mg BID Odds Ratio Symptom [N = 197] [N = 191] Estimate P-Value1.57 0.0182 (1.08, 2.29) 0 47% 35% 1 10% 14% 2 12% 15% 3 15% 20% 4 13%14%

Daily Symptom Score

-   Subjects recorded the following information on dIBS symptoms daily    throughout the duration of the study:    -   Number of normal stools/day;    -   Number of hard and lumpy stools/day;    -   Number of loose or watery stools/day;    -   Number of loose or watery stools/day with the symptom of        urgency;    -   How bothersome is abdominal pain and discomfort? [7-point        response scale: 0 (not at all) to 6 (a very great deal)];    -   How bothersome is bloating? [(7-point response scale: 0 (not at        all) to 6 (a very great deal)].

Changes from baseline variables were computed for each weekly summaryscore.

Long Term Follow-up of Adequate Relief

The study assessed the effect over 12 weeks of follow-up on long-termadequate relief. Subjects who had adequate relief by Week 4 and remainedsymptom-free at Week 5 were followed during the post-treatment phase andshown in FIGS. 1 and 2. Superiority to placebo was maintained during the12 weeks post-treatment follow-up. Results for IBS symptoms were RFX 550mg BID 62.3% versus placebo 49.2%, and RFX 550 mg BID 59.3% versus 50.9%for placebo for the symptom of bloating through week 16. In assessingthe follow-up data, there was statistical significance (p<0.05) ofbloating and IBS symptoms for RFX 550 mg BID versus placebo.

TABLE 6 PBO 4 w RFX 550 2 w Adequate Relief of Bloating, (N = 57) (N =54) Post Treatment n (%) n (%) Week 6 Success 47 (82.5%) 49 (90.7%)Failures 10 (17.5%) 5 (9.3%) Comparison of RFX 550 2 w vs. PBO p-value:0.1303, odds ratio: 3.840 (0.672, 21.95) Week 7 Success 47 (82.5%) 45(83.3%) Failures 10 (17.5%)  9 (16.7%) Comparison of RFX 550 2 w vs. PBOp-value: 0.1311, odds ratio: 2.931 (0.726, 11.84) Week 8 Success 46(80.7%) 47 (87.0%) Failures 11 (19.3%)  7 (13.0%) Comparison of RFX 5502 w vs. PBO p-value: 0.2858, odds ratio: 2.107 (0.536, 8.276) Week 9Success 36 (63.2%) 39 (72.2%) Failures 21 (36.8%) 15 (27.8%) Comparisonof RFX 550 2 w vs. PBO p-value: 0.0814, odds ratio: 2.737 (0.882, 8.492)Week 10 Success 32 (56.1%) 39 (72.2%) Failures 25 (43.9%) 15 (27.8%)Comparison of RFX 550 2 w vs. PBO p-value: 0.0217, odds ratio: 3.828(1.217, 12.04) Week 11 Success 31 (54.4%) 35 (64.8%) Failures 26 (45.6%)19 (35.2%) Comparison of RFX 550 2 w vs. PBO p-value: 0.0398, oddsratio: 3.115 (1.054, 9.205)

TABLE 7 PBO 4 w RFX 550 2 w Adequate Relief of Bloating, (N = 57) (N =54) Post Treatment n (%) n (%) Week 12 Success 32 (56.1%) 36 (66.7%)Failure 25 (43.9%) 18 (33.3%) Comparison of RFX 550 2 w vs. PBO p-value:0.0596, odds ratio: 2.891 (0.958, 8.726) Week 13 Success 29 (50.9%) 33(61.1%) Failure 28 (49.1%) 21 (38.9%) Comparison of RFX 550 2 w vs. PBOp-value: 0.0142, odds ratio: 4.187 (1.333, 13.15) Week 14 Success 29(50.9%) 34 (63.0%) Failure 28 (49.1%) 20 (37.0%) Comparison of RFX 550 2w vs. PBO p-value: 0.0121, odds ratio: 4.230 (1.372, 13.05) Week 15Success 30 (52.6%) 31 (57.4%) Failure 27 (47.4%) 23 (42.6%) Comparisonof RFX 550 2 w vs. PBO p-value: 0.0391, odds ratio: 3.323 (1.062, 10.40)Week 16 Success 29 (50.9%) 32 (59.3%) Failure 28 (49.1%) 22 (40.7%)Comparison of RFX 550 2 w vs. PBO p-value: 0.0212, odds ratio: 3.700(1.216, 11.25)

TABLE 8 Baseline Disease Characteristics Across All Treatment GroupsDaily Symptom Median Min, Max Total No. bowel movements/day 3.0 1, 15No. loose/watery bowel movements/day 2.0 0, 10 No. loose/watery withurgency 1.6 0, 10 Abdominal pain/discomfort* 3.4 0, 6  Bloating* 3.4 0,6  *7 pt. scale asking “How bothersome . . .” [0 = not at all to 6 = avery great deal]

Two measures of efficacy were assessed independently. The first was theproportion of subjects who provided a ‘yes’ response to the weekly SGAquestion: “In the past 7 days, have you had adequate relief of your IBSsymptoms? (yes/no)”. The second endpoint was the proportion of subjectswho provide a ‘yes’ response to the weekly individual symptom question:“In the past 7 days, have you had adequate relief of your symptom ofbloating? (yes/no)”. Durability was based on the proportion of subjectsthat had adequate relief over the entire treatment phase.

TABLE 9 Summary of Correlation between Subjects Satisfied with Relief ofBloating Discomfort and Relief of IBS Symptoms Spearman Number of ReliefResponder Non-Responder Correlation Time Point Subject [1] [2] [2]Coefficient Week 1 680 Yes  49/169 (29.0%) 45/511 (8.8%)  0.2508 No120/169 (71.0%) 458/511 (89.6%)  Missing 8/511 (1.6%) Week 2 680 Yes113/274 (41.2%) 50/406 (12.3%) 0.3218 No 159/274 (58.0%) 327/406(80.5%)  Missing  2/274 (0.7%) 29/406 (7.1%)  Week 3 680 Yes 130/303(42.9%) 48/377 (12.7%) 0.3201 No 169/303 (55.8%) 281/377 (74.5%) Missing  4/303 (1.3%) 48/377 (12.7%) Week 4 680 Yes 145/309 (46.9%)52/371 (14.0%) 0.3362 No 153/309 (49.5%) 252/371 (67.9%)  Missing 11/309(3.6%) 67/371 (18.1%) [1] Responses to the questions ‘How bothersome wasyour bloating today?’ include: 0 = not at all, 1 = hardly, 2 = somewhat,3 = moderately, 4 = a good deal, 5 = a great deal, 6 = a very greatdeal; Relief is score of 0 or 1. [2] Responder is defined as relief ofIBS symptoms.

TABLE 10 Efficacy Analysis: Adequate Relief of IBS Symptoms and Bloatingat the End of the Treatment Phase PBO 4 w RFX 275 2 w RFX 550 2 w RFX1100 2 w RFX 550 4 w (N = 197) (N = 95) (N = 197) (N = 99) (N = 198)Category n (%) n (%) n (%) n (%) n (%) Gender Male Adequate Relief ofIBS Symptoms [1] Success 17 (32.7%)  8 (36.7%) 23 (53.7%) 12 (46.2%)  7(31.3%) Failure 35 (67.3%)  9 (64.8%) 25 (46.3%) 14 (58.8%) 15 (62.2%)Comparison of RFX 550 2 w vs. PBO p-value: 0.0326, odds ratio: 2.511(1.078, 6.842) Adequate Relief of Bloating [2] Success 17 (32.7%)  6(42.5%) 25 (46.3%) 10 (38.8%)  2 (27.3%) Failure 35 (67.3%)  8 (57.1%)29 (53.7%) 16 (61.8%) 16 (72.7%) Comparison of RFX 550 2 w vs. PBOp-value: 0.0802, odds ratio: 2.148 (0.912, 5.057) Female Adequate Reliefof IBS Symptoms [1] Success 70 (48.3%) 35 (46.2%) 71 (61.8%) 23 (39.7%)34 (44.7%) Failure 75 (51.7%) 46 (56.3%) 86 (42.2%) 44 (60.3%) 42(55.3%) Comparison of RFX 550 2 w vs. PBO p-value: 0.7608, odds ratio:1.078 (0.665, 1.747) Adequate Relief of Bloating [2] Success 81 (42.1%)29 (35.3%) 83 (46.0%) 28 (33.4%) 32 (42.1%) Failure 84 (57.9%) 52(64.2%) 74 (54.0%) 45 (61.6%) 44 (87.3%) Comparison of RFX 550 2 w vs.PBO p-value: 0.5866, odds ratio: 1.166 (0.716, 1.998) [1] Subjectsachieved success if they reported a ‘yes’ response to whichever questionabout IBS symptoms was posed by the IVR system(i.e. adequate relief orcontrol) for = 2 out of the 3 final treatment weeks. [2] Subjectsachieved success if they reported a ‘yes’ response to whichever questionabout symptoms of bloating was posed by the IVR system (i.e. adquaterelief or control) for = 2 out of the 3 final treatment weeks.The treatment effect is more pronounced when accounting for milderdisease severity, i.e., bloating, abdominal pain/discomfort and bowelmovements.

Example 2

A study (FIG. 3) is designed to evaluate the efficacy of a 14-day courseof oral rifaximin at 550 mg TID in providing adequate relief fromdiarrhea-associated IBS (dIBS) symptoms over four weeks. A measure ofefficacy is based on subjects' answers to the Weekly Subject GlobalAssessment (SGA) questions over the 4 week study duration in relation totheir IBS symptoms. The SGA question is asked weekly as follows: “In thepast 7 days, have you had adequate relief of your IBS symptoms?”(Yes/No.) Subjects in the treatment group taking oral rifaximin respond“Yes” more often than Subjects who are not taking oral rifaximin.Another measure of efficacy is based on subjects' answers to the WeeklySubject Global Assessment (SGA) question over the 4 week study durationin relation to their IBS symptom of bloating. The SGA question is askedweekly as follows: “In the past 7 days, have you had adequate relief ofyour IBS symptom of bloating?” (Yes/No. Subjects in the treatment grouptaking oral rifaximin respond “Yes” more often than subjects who are nottaking oral rifaximin. Other measures of efficacy include the changes indIBS symptoms from baseline to each week of the 4 weeks in the study(e.g., abdominal pain and discomfort, bloating, number of stools perday, stool consistency, urgency with loose or watery stools).

Example 3 Improvements in Quality of Life

A study showed the rifaximin 550 mg twice daily (BID) significantlyimproved IBS symptoms versus placebo in patients withdiarrhea-predominant IBS (IBS-D). Analyses from that study evaluated theefficacy of rifaximin for improving quality of life (QOL) measures inpatients with IBS-D.

Adults diagnosed with IBS-D (Rome II criteria) received rifaximin 550 mgBID or placebo for 14 days. Both groups received placebo for anadditional 14 days after the initial 2-week treatment. Quality of lifewas assessed with the 34-item IBS-QOL questionnaire at baseline and 4weeks after initiating treatment. Each item was scored on a 5-pointscale (1=not at all; 2=slightly; 3=moderately; 4=quite a bit; and5=extremely or a great deal). Results for composite and subscale scoreswere converted to a scale ranging from 0 to 100, with higher scoresindicating better QOL.

A total of 388 patients were treated; 191 patients received rifaximinand 197 patients received placebo during the 2-week initial treatmentperiod. The mean improvement from baseline in overall QOL scores at week4 was significantly greater with rifaximin compared with placebo (Table11). Patients in the rifaximin group reported significantly greater meanimprovement from baseline in QOL scores for dysphoria, body image,health worry, social reaction, and relationship subscales compared withplacebo (Table 11). Rifaximin was well tolerated, with similar incidenceof adverse events compared with placebo.

In patients with IBS-D, rifaximin 1100 mg/d for 14 days significantlyimproved QOL measures compared with placebo. These findings suggest apotential therapeutic role for rifaximin 550 mg BID for improvingsymptoms and QOL in patients with IBS-D and are summarized in Table 11.

TABLE 11 Mean Change From Baseline in IBS-QOL Scores at Week 4Improvement with Rifaximin 1100 Placebo rifaximin over P Domain mg/d (n= 191) (n = 197) placebo, % value Overall score 20.4 15.8 28.7 0.020Dysphoria 24.8 19.8 25.3 0.027 Interference 22.2 18.1 22.2 0.083 withactivity Body image 20.1 14.6 37.4 0.012 Health worry 16.0 12.2 30.60.047 Food avoidance 25.0 20.5 22.1 0.088 Social reaction 17.3 13.2 31.60.047 Sexual 13.6 10.9 24.9 0.199 Relationship 14.9 10.7 39.5 0.030

A 2-week course of rifaximin (1100 mg/day) significantly improvedquality of life (QOL) measures, compared with placebo.

In a study, 191 adult patients diagnosed with diarrhea-predominant IBS(IBS-D) by Rome II criteria were randomized to receive rifaximin 550 mgtwice daily (BID) and 197 patients were randomized to placebo. Followinga 2-week initial treatment period, both groups of patients receivedplacebo for an additional 14 days. Quality of life was assessed via the34-item IBS-QOL questionnaire at baseline and 4 weeks after initiatingtreatment. Each item was scored on a 5-point scale (1=not at all;2=slightly; 3=moderately; 4=quite a bit; 5=extremely or a great deal);results for composite and subscale scores were converted to a scaleranging from 0 to 100, with higher scores indicating better QOL.

At Week 4, the mean improvement from baseline in the overall QOL scorewas significantly greater with rifaximin compared with placebo (20.4 vs.15.8, respectively; p=0.020). Patients in the rifaximin group alsoreported significantly greater mean improvement from baseline in QOLsubscale scores for dysphoria (restlessness or agitation, 24.8 vs. 19.8;p=0.027), body image (20.1 vs. 14.6; p=0.012), health worry (16.0 vs.12.2; p=0.047), social reaction (17.3 vs. 13.2; p=0.047), andrelationships (14.9 vs. 10.7; p=0.030), compared with placebo. Rifaximinwas well tolerated in the study, with a similar incidence of adverseevents compared with placebo.

Example 4 Severity of Baseline Symptoms as Predictor of ClinicalResponse

It is reported herein that the severity of baseline symptoms ofabdominal pain and bloating influenced the response to rifaximintreatment. The co-primary endpoints in this analysis assessed weeklyyes/no responses to questions regarding adequate relief of global IBSsymptoms and IBS-associated bloating. Severity of baseline IBS symptomswas evaluated as a potential confounder of clinical response and wascategorized as mild/moderate or severe based on a mean score of ≦4vs. >4 (on a 7-point scale) for bloating and abdominal pain.

A significantly larger percentage of patients treated with rifaximinreported adequate relief of global IBS symptoms (52% vs. 44% forplacebo; p=0.03) and bloating (46% vs. 40%; p=0.04), compared withplacebo-treated patients. In patients with mild/moderate abdominal pain,rifaximin produced a greater degree of improvement, compared withplacebo, in global symptoms of IBS (50% vs. 39%, respectively; p=0.04)and bloating (44% vs. 35%; p=0.09). Similarly, in patients withmild/moderate bloating, rifaximin treatment was associated with greaterimprovement, compared with placebo, in global IBS symptoms (56% vs. 41%,respectively; p=0.006) and bloating (47% vs. 36%; p=0.03). Thisdemonstrates that patients with mild/moderate IBS symptoms are morelikely than those with severe disease to achieve symptomatic relief withrifaximin.

These results show that rifaximin improves gastrointestinal (GI)symptoms associated with IBS. In this study of rifaximin versus placebo,patients with diarrhea-predominant IBS (IBS-D) were studied, asupplemental analysis examined the association between severity ofbaseline IBS symptoms and clinical response to rifaximin.

A comparison involved 2 groups of adult patients with IBS-D (Rome II)who received rifaximin 550 mg twice daily or placebo for 14 days,followed by an additional 14 days of placebo in both groups. The Weeklyyes/no responses to questions regarding adequate relief of global IBSsymptoms and IBS-associated bloating were assessed. Clinical responsewas defined as adequate relief for 2 of the final 3 treatment weeks (wk2, 3, or 4). Severity of baseline IBS symptoms was evaluated as apotential confounder of clinical response and was categorized asmild/moderate or severe based on a mean score of ≦4 versus >4 (on a7-point scale (0=not bothersome; 6=very bothersome)) for bloating andabdominal pain.

A significantly larger percentage of patients who received rifaximinversus placebo reported adequate relief of global IBS symptoms (52%versus 44%, respectively; P=0.03) and bloating (46% versus 40%,respectively; P=0.04). In patients with mild/moderate abdominal pain,rifaximin produced a greater degree of improvement versus placebo insymptoms of IBS (50% versus 39%, respectively; P=0.04) and bloating (44%versus 35%, respectively; P=0.09). In patients with mild/moderatebloating, rifaximin also achieved greater improvement versus placebo inglobal symptoms of IBS (56% versus 41%, respectively; P=0.006) andbloating (47% versus 36%, respectively; P=0.03). Severity of baselinesymptoms of abdominal pain and bloating influenced the response torifaximin 1100 mg/d for 14 days. Patients with mild/moderate IBSsymptoms had a greater likelihood of relief of global IBS-relatedsymptoms with rifaximin treatment versus individuals with severe IBSsymptoms.

INCORPORATION BY REFERENCE

The contents of all references, patents, pending patent applications andpublished patents, cited throughout this application are herebyexpressly incorporated by reference.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

What is claimed is:
 1. A method of treating symptoms ofdiarrhea-associated Irritable Bowel Syndrome (dIBS) in a subject, saidmethod comprising orally administering to the subject a dosage formcomprising 550 mg of rifaximin three times per day for 14 days to thesubject in need thereof, wherein said symptoms consist of diarrhea andone or more selected from the group consisting of cramping, abdominalpain, abdominal discomfort, and frequent stool production.
 2. The methodof claim 1, wherein the subject is human.
 3. The method of claim 2,wherein the subject is an adult.
 4. The method of claim 1, wherein thedosage form is a tablet.
 5. The method of claim 1, wherein the dosageform comprises more than one rifaximin polymorph.
 6. The method of claim5, wherein the dosage form comprises rifaximin alpha polymorph.